The Optispan Podcast with Matt Kaeberlein

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In our fifth episode of the R-Files, Matt shares insights from his recent course of off-label rapamycin use, which he started in January 2024 and plans to continue for at least the next month or two. He describes improvements in joint pain and body fat loss as well as an unexpected bacterial infection, and speculates about whether rapamycin may have contributed to any of these effects. He also discusses rapamycin's half-life in his blood, which is significantly lower than that reported in the published literature.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients

Sirolimus is the common name for the pharmaceutical formulation of rapamycin, so for our purposes we can consider sirolimus and rapamycin to be interchangeable. This paper reports an elimination half-life of 63 hours for sirolimus, which means it should take around 63 hours for the concentration of the drug in the bloodstream to decrease by half. After another 63 hours, half of the remaining drug should be eliminated, and so on, until the drug is cleared from the body. The half-life of a drug can vary depending on factors such as an individual's metabolism, the route of administration, and whether an individual takes the drug regularly, and is an important pharmacokinetic parameter that helps determine dosing frequency and duration of action.

Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

This paper reports a rapamycin half-life of 58–63 hours, or around three days.


Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

This study found that administering a single dose of rapamycin to rats was enough to inhibit their food intake and daily weight gain in the first three to five days post-injection, with a greater reduction observed for higher rapamycin doses. The rapamycin dose also brought about a body weight reduction that lasted for about two months without any additional rapamycin injection. The authors speculate that the effect may be due to a rapamycin-induced change in body weight set point. A single rapamycin dose did not induce any glucose tolerance changes in the rats.


Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats

This study also reported inhibited food intake and weight loss in rats receiving rapamycin, but found that rapamycin also brought about various metabolic defects including glucose intolerance (difficulties metabolizing glucose), hyperinsulinemia (too much insulin in the blood), and hyperglycemia (too much sugar in the blood). These defects were particularly pronounced in rats eating a high-fat diet.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In the third episode of the R-Files, Matt, who studied rapamycin for over a decade of his career, talks about a recent study evaluating the benefits and side effects of taking rapamycin off-label—that is, for a purpose other than that for which the drug gained FDA approval. Physicians can prescribe any FDA-approved drug off-label as long as they believe it will be beneficial for the patient. Matt discusses noteworthy potential side effects of rapamycin use, the experiences of study participants who took rapamycin, and why off-label rapamycin use is not widespread despite considerable evidence for life- and healthspan benefits in laboratory animals.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin News

Many of our podcast listeners are interested in questions about rapamycin dosing, how to get a prescription for rapamycin, and how rapamycin might interact with other supplements or drugs. This website is a great resource for getting more clarity on some of these questions, as well as for hearing about others' experiences with rapamycin and other longevity medications.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

Rapamycin and aging: Dosage, side effects, and success stories | Matt Kaeberlein

Matt discusses rapamycin on this podcast with Stanford Prevention Research Center lecturer Lucia Aronica. He makes several anecdotal observations about rapamycin, including that most people don’t seem to experience observable side effects on a weekly 3-6 mg dose. Side effects that seem real, he notes, are mouth sores and higher triglycerides. He also discusses differences in side effects observed in biohackers versus organ transplant patients taking rapamycin.

Rapamycin in aging and disease: maximizing efficacy while minimizing side effects

This article argues for several important considerations in future studies of rapamycin for successful translation to human use, including sex-dependent impacts on biological outcomes, the impact of short-term rapamycin treatment on a variety of healthspan metrics, the best regimen for extracting maximum benefits from rapamycin treatment while minimizing adverse effects, and more.

mTOR Inhibition: From Aging to Autism and Beyond

In this paper, Matt reviews the effects of mammalian target of rapamycin (mTOR) inhibitors on age-related disease and decline as well as on non-aging-related diseases such as tuberous sclerosis complex and epilepsy. He describes the side effects of chronic mTOR inhibition in mice, which include hyperlipidemia, insulin resistance, enhanced cataract formation and male sterility; as well as the adverse effects of mTOR inhibitors used in the clinic, which include mouth ulcers, diarrhea and nausea, hyperlipidemia, and infection.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In the fourth episode of the R-Files, Matt discusses research demonstrating that rapamycin rejuvenates the aged mouse immune system to respond to a flu vaccine as if it were in a youthful state. He also discusses papers suggesting that rapamycin may have similar effects on human immune systems.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

This is the study that Matt describes at the beginning of this episode as one of the first demonstrations of lifespan extension via a treatment that starts in middle age. Researchers found that rapamycin improved mouse survival by 14% and 9% for females and males respectively, even when rapamycin feeding began late in life. The authors propose several mechanisms by which rapamycin might delay aging, including modulation of nutrient dynamics and cellular stress resistance.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

Lots of big immunology words in this one—thankfully, Matt breaks them down for us in the podcast. This paper focuses on mouse hematopoietic stem cells (HSCs), which are cells that give rise to all types of blood cells. It describes two core findings that, taken together, strengthen the evidence for the role of mTOR (mammalian target of rapamycin) signalling in HSC aging. First, genetic manipulation in young mice over-activates mTOR activity and leads to an aged mouse HSC phenotype; and second, rapamycin rejuvenates HSC function, improves vaccination response, and increases lifespan.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Many of those interested in rapamycin have questions about what the optimum rapamycin dosing regime looks like. While there is not yet any conclusive evidence suggesting an ideal dose for humans, researchers have demonstrated dosing regimes that work in mice. This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects, validating previous work on this question.

TORC1 inhibition enhances immune function and reduces infections in the elderly

This paper investigated the effects of rapamycin treatment on elderly humans. It found that a rapamycin derivative improved vacination response and decreased infection rates in healthy people over 65, with minimal adverse effects.

Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

This study describes a clinical trial of an oral mTOR inhibitor’s effects on antiviral immunity in people aged over 65. Patients who took the drug demonstrated a greater upregulation of antiviral responses compared to those who took a placebo drug. Those receiving the mTOR inhibitor also suffered from fewer respiratory tract infections, including coronavirus, rhinovirus, and the flu.

You asked, we listened. Ever since the February 2024 launch of our series "The R-Files", a series of episodes about all things rapamycin, we've received a ton of questions about this compound and how it works in the context of aging and longevity. We went through every comment you left on Youtube, Twitter, and LinkedIn to compile a list of your questions about combining interventions, optimizing rapamycin dosing, limitations in applying findings from mice and medical studies to off-label human usage of rapamycin and other supplements, and so much more.

Keep the questions coming—if there are more, we'll address them in a future AMA episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin News

Many of our podcast listeners are interested in questions about rapamycin dosing, how to get a prescription for rapamycin, and how rapamycin might interact with other supplements or drugs. This website is a great resource for getting more clarity on some of these questions, as well as for hearing about others' experiences with rapamycin and other longevity medications.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

This study addresses the question of how much the effects of rapamycin recapitulate the effects of caloric restriction by profiling gene expression signatures and markers of muscle quality in mice undergoing caloric restriction and rapamycin treatment. The researchers found that rapamycin and caloric restriction likely act via mechanisms that are likely non-overlapping and complementary in mouse skeletal muscle.

Effect of caloric restriction and rapamycin on ovarian aging in mice

This study found that caloric restriction and rapamycin exert similar effects on ovarian aging in mice. Both interventions preserve the number of primordial follicles—immature egg cells at the earliest stage of ovarian follicle development—to a similar degree. Effects on metabolism differed, however: caloric restriction mice demonstrated lower weight gain and visceral fat as well as increased insulin sensitivity, while rapamycin-treated mice did not.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In this first episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, will discuss how fortuitous conversations, an appetite for unexplored territory, and an opportunity to look where others weren't looking helped him get deep into the study of rapamycin and uncover some interesting insights into how rapamycin can affect lifespan.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle

Published in 1975, this landmark paper describes the discovery of a new antifungal antibiotic called rapamycin, and characterizes rapamycin's morphological, physiological, and cultural properties and the streptomycete strain that produces it. It detailsthe isolation of the streptomycete strain AY B-994 from an Easter Island soil sample as well as the strain's antimicrobial activity.

Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients

This 2005 paper was the first to describe the molecular pathway by which caloric restriction could influence yeast lifespan. Caloric restriction extended yeast replicative lifespan—that is, the number of times a yeast cell can divide and produce daughter cells before it stops dividing—by downregulating signaling through TOR1 and Sch9 genes. In yeast, the TOR1 gene codes for the TOR1 protein, a protein analogous to the mTOR protein in mice. Rapamycin inhibits mTOR1.

Extension of chronological life span in yeast by decreased TOR pathway signaling

This is the experiment involving nearly 5,000 yeast strains that Matt describes in the podcast.

The discovery & first uses of rapamycin | Peter Attia, David Sabatini, & Matt Kaeberlein

Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini in this rapamycin-themed episode of the Peter Attia Drive podcast. In this clip, three longevity experts dig into the history of rapamycin’s discovery. They also discuss rapamycin’s clinical path as an immunosuppressant and how that path may have impacted the development of rapamycin for other uses, the decades-long gap between the discovery of rapamycin and its eventual use in the clinic, and the difficulty of disentangling side effects that come from rapamycin use versus that of other drugs.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In this second episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, discusses his own journey to using rapamycin off-label and how it all began with a persistent pain in his right shoulder that a doctor suggested might take a year to resolve. Matt conducted an n=1 experiment to test whether a short course of rapamycin might improve the age-related inflammation that was the likely cause of his shoulder issue.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

mTOR is a key modulator of ageing and age-related disease

This paper reviews the mechanistic target of rapamycin (mTOR) pathway, a nutrient sensing pathway that shows promise as a target for interventions to increase life- and healthspan. The mTOR pathway acts as a control center that helps cells decide what to do based on the nutrients available. When nutrients are abundant, mTOR tells cells to grow and divide; when nutrients are scarce, it signals cells to conserve energy and not grow too much. The article delves into the mechanisms by which the mTOR pathway influences longevity, including mRNA translation, autophagy, stress resistance and xenobiotic metabolism, mitochondrial function, inflammation, and stem cell rejuvenation.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

The age-associated decline in function of hematopoietic stem cells (HSCs), cells in the bone marrow that give rise to all types of blood cells in the body, can lead to issues such as anemia and increased cancer risk. This study demonstrates that the mTOR pathway in HSCs is more active in older mice than in younger mice, and that activating this pathway accelerated HSC aging in young mice. Treating older mice with rapamycin, an mTOR inhibitor, extended their life- and healthspan. Taken together, these findings provide further evidence to suggest that the mTOR pathway plays a key role in aging.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Many of those interested in rapamycin have questions about what the optimum rapamycin dosing regime looks like. While there is not yet any conclusive evidence suggesting an ideal dose for humans, researchers have demonstrated dosing regimes that work in mice. This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects.

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

This study found that rapamycin improved mouse survival by 14% and 9% for females and males respectively, even when rapamycin feeding began late in life. The authors propose several mechanisms by which rapamycin might delay aging, including modulation of nutrient dynamics and cellular stress resistance.

272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more

In this episode of the Peter Attia Drive podcast, Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini to talk about the discovery of rapamycin, its first uses in humans, the mTOR pathway, potential mechanisms by which rapamycin might influence human longevity, recent studies of the effects of rapamycin in model organisms, potential side effects, and more.